Alternative titles; symbols
HGNC Approved Gene Symbol: CD28
Cytogenetic location: 2q33.2 Genomic coordinates (GRCh38): 2:203,706,482-203,738,912 (from NCBI)
CD28 costimulation is essential for CD4 (186940)-positive T-cell proliferation, survival, interleukin-2 (IL2; 147680) production, and T-helper type-2 (Th2) development.
Monoclonal antibodies recognize 3 antigens, CD3 (186790), CD2 (186990), and CD28 (Tp44), that cause human T cells to proliferate in the presence of phorbol esters. Whereas CD3 appeared to be involved in transduction of the signal generated by antigen binding to the T-cell receptor, the role of the CD2 and CD28 antigens in physiologic proliferation was not understood. Aruffo and Seed (1987) isolated a cDNA clone encoding CD28 by a simple and highly efficient cloning strategy based on transient expression. In COS cells the CD28 encodes a highly glycosylated membrane protein with homology to the immunoglobulin superfamily.
Magistrelli et al. (1999) identified 3 CD28 splice variants in nonactivated T cells: CD28a, which lacks exon 3, leading to loss of the transmembrane domain; CD28b, which lacks most of the 3-prime end of exon 2 and exon 3; and CD28c, which lacks exon 2 and exon 3. CD28b and CD28c were expressed at a low level relative to CD28a. Magistrelli et al. (1999) suggested that resting T cells may constitutively express both membrane and soluble CD28, potentially regulating the T-cell response at different levels.
Harada et al. (2003) noted that the CD28 cytoplasmic domain contains a YMNM motif, which binds PI3K (see 601232) and GRB2 (108355), whereas the corresponding region of ICOS (604558) contains a YMFM motif, which binds the former but not the latter. Harada et al. (2003) hypothesized that the reason CD28 signaling, but not ICOS signaling, induces IL2 production is its ability to bind GRB2. To test this hypothesis, they generated mutant ICOS containing the YMNM motif of CD28. This alteration allowed ICOS to activate the IL2 promoter, and further analysis showed that GRB2 binding to ICOS led to activation of the NFAT (see 600490)/AP1 (165160) site in the IL2 promoter. Harada et al. (2003) concluded that the difference of a single amino acid defines a functional difference between CD28- and ICOS-mediated costimulatory signals.
By a comprehensive structure-function analysis of the mouse Cd28 cytoplasmic tail, Andres et al. (2004) found that Il2 production and T-cell proliferation did not require a particular cytoplasmic domain. However, Il4 (147780) production was driven by cooperative activity of at least 2 structural motifs, a pro-rich motif at residues 187 to 190 and tyr residues at positions 170 and 188, within the Cd28 cytoplasmic tail. A gene complementation approach determined that Pdk1 (605213), but not Itk (186973) or Akt (164730), in an Akt-independent pathway, mediated a component of the Il4 signal induced by Cd28.
CTLA4 shares 2 ligands, CD80 (112203) and CD86 (601020), with a stimulatory receptor, CD28. Qureshi et al. (2011) showed that CTLA4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. Qureshi et al. (2011) concluded that their data revealed a mechanism of immune regulation in which CTLA4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the features of the CD28-CTLA4 system.
Kamphorst et al. (2017) demonstrated that the CD28/B7 costimulatory pathway is essential for effective PD1 (600244) therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T-cell proliferation after PD1 blockade. B7 costimulation was also necessary for effective PD1 therapy in tumor-bearing mice. In addition, Kamphorst et al. (2017) found that CD8 T cells proliferating in blood after PD1 therapy of lung cancer patients were predominantly CD28-positive. Kamphorst et al. (2017) concluded that their data demonstrated a CD28 costimulation requirement for CD8 T-cell rescue and suggested an important role for the CD28/B7 pathway in PD1 therapy of cancer patients.
By titrating PD1 signaling in a biochemical reconstitution system, Hui et al. (2017) demonstrated that the coreceptor CD28 is strongly preferred over the T cell receptor (TCR; see 186880) as a target for dephosphorylation by PD1-recruited Shp2 (176876) phosphatase. Hui et al. (2017) also showed that CD28, but not the TCR, is preferentially dephosphorylated in response to PD1 activation by PDL1 (605402) in an intact cell system. Hui et al. (2017) concluded that PD1 suppresses T-cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T-cell function and responses to anti-PDL1/PD1 therapy.
Lee et al. (1990) found that the CD28 gene is present in single copy and is organized into 4 exons, each of which defines a functional domain of the predicted protein. Posttranslational processing appears to result in variant isotypes of CD28 with potentially different physiologic roles on the cell surface.
Using in situ hybridization on prometaphase cells, Lafage-Pochitaloff et al. (1990) demonstrated that the CD28 gene maps to 2q33-q34. The CTLA4 gene (123890) maps to the same region. Both are members of the Ig superfamily, where they define a subgroup of membrane-bound single V domains. The chromosomal proximity of CD28 and CTLA4 and their close structural relationship suggest that these 2 genes resulted from duplication of a common evolutionary precursor and that they share some functional properties. By means of intersubspecific crosses, Howard et al. (1991) mapped the Cd28 gene to the proximal part of mouse chromosome 1. By study of yeast artificial chromosomes (YAC), Buonavista et al. (1992) demonstrated that the CD28 and CTLA4 genes were in the same fragment, indicating that they were separated by only 25 to 150 kb. A CpG island was found between these genes.
CD28 undergoes tyrosine phosphorylation after interacting with its ligand, B7 (CD80; 112203). Phosphorylation of tyr173 (tyr170 in mouse) in the cytoplasmic domain of CD28 allows the recruitment of signaling proteins such as phosphatidylinositol 3-kinase (see PIK3R1; 171833), GRB2 (108355), and GADS (GRAP2; 604518) via their SH2 domains. Okkenhaug et al. (2001) reconstituted CD28 knockout mice with transgenes encoding wildtype Cd28 or Cd28 carrying a tyr170-to-phe mutation. Mutant Cd28 did not bind to the SH2 domain of PIK3R1, resulting in diminished protein kinase B (164730) activation. Mutant Cd28 was able to prevent the induction of anergy, to promote T-cell proliferation and IL2 secretion, and to provide B-cell help, but was unable to upregulate expression of the prosurvival protein BCLXL (600039). The defect in BCLXL upregulation was correlated with increased susceptibility of the T cells to gamma radiation. Okkenhaug et al. (2001) suggested that other tyrosine residues or asn172 may be critical to functions not affected by the tyr170-to-phe mutation.
Akieda et al. (2015) had previously shown that transfer of Cd28-deficient T cells did not induce chronic graft-versus-host disease (cGVHD; see 614395) in mice. They found that Cd28-deficient recipients of wildtype T cells developed cGVHD, but in a different form than that observed in wildtype recipients. Instead of a type of cGVHD resembling systemic lupus erythematosus (SLE; 152700), Cd28-deficient hosts developed fibrotic damage in skin and internal organs resembling that of systemic sclerosis (SS; see 181750). Using various Cd28 transgenic strains, the authors showed that a lack of signaling through the C-terminal proline-rich motif within the Cd28 cytoplasmic tail was the cause of the phenotype. This Cd28 motif is required for development of regulatory T cells (Tregs) and for the function of conventional T cells. Adoptive transfer studies demonstrated that a defect in host Cd4-positive/Cd25 (IL2RA; 147730)-positive Tregs, but not conventional T cells, was responsible for SS-type cGVHD. The host Treg deficiency altered the cytokine pattern of donor Cd4-positive T cells and the antigen specificity of autoantibodies, possibly leading to the change in phenotype. Akieda et al. (2015) concluded that CD28 signaling controls the pathogenesis of cGVHD through effects on host Tregs, whose status impacts qualitatively on allogeneic immune responses.
Akieda, Y., Wakamatsu, E., Nakamura, T., Ishida, Y., Ogawa, S., Abe, R. Defects in regulatory T cells due to CD28 deficiency induce a qualitative change of allogeneic immune response in chronic graft-versus-host disease. J. Immun. 194: 4162-4174, 2015. [PubMed: 25825447] [Full Text: https://doi.org/10.4049/jimmunol.1402591]
Andres, P. G., Howland, K. C., Nirula, A., Kane, L. P., Barron, L., Dresnek, D., Sadra, A., Imboden, J., Weiss, A., Abbas, A. K. Distinct regions in the CD28 cytoplasmic domain are required for T helper type 2 differentiation. Nature Immun. 5: 435-442, 2004. [PubMed: 15004555] [Full Text: https://doi.org/10.1038/ni1044]
Aruffo, A., Seed, B. Molecular cloning of a CD28 cDNA by a high-efficiency COS cell expression system. Proc. Nat. Acad. Sci. 84: 8573-8577, 1987. [PubMed: 2825196] [Full Text: https://doi.org/10.1073/pnas.84.23.8573]
Buonavista, N., Balzano, C., Pontarotti, P., Le Paslier, D., Golstein, P. Molecular linkage of the human CTLA4 and CD28 Ig-superfamily genes in yeast artificial chromosomes. Genomics 13: 856-861, 1992. [PubMed: 1322357] [Full Text: https://doi.org/10.1016/0888-7543(92)90169-s]
Harada, Y., Ohgai, D., Watanabe, R., Okano, K., Koiwai, O., Tanabe, K., Toma, H., Altman, A., Abe, R. A single amino acid alteration in cytoplasmic domain determines IL-2 promoter activation by ligation of CD28 but not inducible costimulator (ICOS). J. Exp. Med. 197: 257-262, 2003. [PubMed: 12538664] [Full Text: https://doi.org/10.1084/jem.20021305]
Howard, T. A., Rochelle, J. M., Seldin, M. F. Cd28 and Ctla-4, two related members of the Ig supergene family, are tightly linked on proximal mouse chromosome 1. Immunogenetics 33: 74-76, 1991. [PubMed: 1671668] [Full Text: https://doi.org/10.1007/BF00211698]
Hui, E., Cheung, J., Zhu, J., Su, X., Taylor, M. J., Wallweber, H. A., Sasmal, D. K., Huang, J., Kim, J. M., Mellman, I., Vale, R. D. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355: 1428-1433, 2017. [PubMed: 28280247] [Full Text: https://doi.org/10.1126/science.aaf1292]
Kamphorst, A. O., Wieland, A., Nasti, T., Yang, S., Zhang, R., Barber, D. L., Konieczny, B. T., Daugherty, C. Z., Koenig, L., Yu, K., Sica, G. L., Sharpe, A. H., Freeman, G. J., Blazar, B. R., Turka, L. A., Owonikoko, T. K., Pillai, R. N., Ramalingam, S. S., Araki, K., Ahmed, R. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355: 1423-1427, 2017. [PubMed: 28280249] [Full Text: https://doi.org/10.1126/science.aaf0683]
Lafage-Pochitaloff, M., Costello, R., Couez, D., Simonetti, J., Mannoni, P., Mawas, C., Olive, D. Human CD28 and CTLA-4 Ig superfamily genes are located on chromosome 2 at bands q33-q34. Immunogenetics 31: 198-201, 1990. [PubMed: 2156778] [Full Text: https://doi.org/10.1007/BF00211556]
Lee, K. P., Taylor, C., Petryniak, B., Turka, L. A., June, C. H., Thompson, C. B. The genomic organization of the CD28 gene: implications for the regulation of CD28 mRNA expression and heterogeneity. J. Immun. 145: 344-352, 1990. [PubMed: 2162892]
Lesslauer, W., Gmunder, H., Bohlen, P. Purification and N-terminal amino acid sequence of the human T90/44 (CD28) antigen. Immunogenetics 27: 388-391, 1988. [PubMed: 2833438] [Full Text: https://doi.org/10.1007/BF00395136]
Magistrelli, G., Jeannin, P., Elson, G., Gauchat, J.-F., NGuyen, T. N., Bonnefoy, J.-Y., Delneste, Y. Identification of three alternatively spliced variants of human CD28 mRNA. Biochem. Biophys. Res. Commun. 259: 34-37, 1999. [PubMed: 10334911] [Full Text: https://doi.org/10.1006/bbrc.1999.0725]
Okkenhaug, K., Wu, L., Garza, K. M., La Rose, J., Khoo, W., Odermatt, B., Mak, T. W., Ohashi, P. S., Rottapel, R. A point mutation in CD28 distinguishes proliferative signals from survival signals. Nature Immun. 2: 325-332, 2001. [PubMed: 11276203] [Full Text: https://doi.org/10.1038/86327]
Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., Hou, T. Z., Futter, C. E., Anderson, G., Walker, L. S. K., Sansom, D. M. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332: 600-603, 2011. [PubMed: 21474713] [Full Text: https://doi.org/10.1126/science.1202947]